The present invention is novel compounds which are 4,6-di-tertiary-butyl-5-hydroxy-1, 3-pyrimidine substituted 1,2,4- and 1,3,4-thiadazoles and oxadiazoles, and 1,2,4-triazoles, and pharmaceutically acceptable acid addition or base salts thereof, pharmaceutical compositions and methods of use therefor. The invention compounds are now found to have activity as inhibitors of 5-lipoxygenase and/or cyclooxygenase providing treatment of conditions advantageously affected by such inhibition including inflammation, arthritis, pain, fever, and particularly rheumatoid arthritis, osteoarthritis, other inflammatory conditions, psoriasis, allergic diseases, asthma, inflammatory bowel disease, GI ulcers, cardiovascular conditions, including ischemic heart disease and atherosclerosis, and ischemia-induced cell damage, particularly brain damage caused by stroke. They can also be used topically for treating acne, sunburn, psoriasis, and eczema. Also included are leukotriene mediated pulmonary, gastrointestinal, inflammatory, dermatological, and cardiovascular conditions. The disclosed compounds also have potential utility as antioxidants. The preferred use is in treating inflammatory conditions. Thus, the present invention is also a pharmaceutical composition or method of manufacturing a pharmaceutical composition for the use of treating the noted conditions.
3,5-Ditertiarybutyl-4-hydroxyphenyl substituted 1,2,4- and 1,3,4-thiadiazoles and oxadiazoles, and 1,2,4-triazoles are known to provide activity as inhibitors of 5-lipoxygenase and/or cyclooxygenase. See U.S. application Ser. No. 07/277,171, filed Nov. 29, 1988, now abandoned, and U.S. application Ser. No. 07/426/814, filed Oct. 30, 1989, now pending. Pyrimidine is not noted in this reference. Structure activity relationships of certain ditertiaryphenols and homologs thereof are discussed by Lazer, E. S., et al in "Effect of Structure on Potency and Selectivity in 2,6-Disubstituted 4-(2-Arylethenyl)phenol Lipoxygenase Inhibitors of J. Med. Chem. 1990, 33, 1892-1998. Again, pyrimidines are not noted in this reference and so compounds therein differ from the present invention.
Numerous references disclose 2-amino-5-hydroxy pyrimidines. Compounds having other N containing groups in place of the amino are also disclosed, however, in each such compound all attachments are through the N. Such disclosed pyrimidines may also be substituted at the 4- and/or 6-positions with various groups including alkyls. No reference shows a tertiarybutyl in both the 4- and the 6-positions in combination with a 5-hydroxy together with any group other than the N or S containing substituent in the 2-position as now found in the present invention. For example, UK patent application number 2045736 and the Bioch. J. 1951, 48, p. 400 shows the simple 2-amino-5-hydroxy-4,6-dimethylpyrimidine. Other substituted 2-aminopyrimidines are shown in European patent application numbers 89312736.5 and 86305466.4 (equivalent to U.S. Pat. No. 4,711,888), European publication numbers 319170, 233416, 164204, and U.S. Pat. Nos. 4,859,679 and 4,940,712.
Japanese Application No. 1,216, 978 discloses 2-arylpyrimidines but differs from the present invention, that requires the 4,6-ditertiarybutyl-5-hydroxy substituents.
The difficulty of accommodating steric hindrance in the synthesis of 4,6-ditertiarybutyl substituted pyrimidine N-oxide is documented in J. C. S. Perkin I (1976) 1202-4. No 5-OH is considered in this synthesis. Further, although French Application No. 1,476,534 presents a generic scope including various 2-substituted pyrimidines this French application differs from the present invention by failing to provide the present invention substituent combinations.
The disclosures in Chem. Ber. (1960) , p. 1998-2001 and in The Indian Journal of Chemistry, Vol. 24B, May 1985, pp. 535-538, showing oxazole to pyrimidine ring transformations and the disclosure in Chemical Reviews 1975, Vol. 75, No. 4, pp. 207 and 412 showing a preparation of an oxazole and subsequent transformation to pyrimidine all show a synthesis and product having substituents in the 4- and 6-positions offering little or no steric hindrance contrary to the present invention which contains 4,6-ditertiarybutyl together with a 5-hydroxy substituent.
In summary, the references of record show neither the present 2-substituent nor combinations of 4- and 6-substituents with a 5-hydroxy group and particularly combinations in which the 4- and 6-substituents are ditertiarybutyl groups which provide steric hindrance during synthesis of pyrimidines.
In fact, there are numerous references showing 4,6-dimethyl-5-hydroxy-2-substituted pyrimidines.
Thus, the references of the prior art differ from that as set out in the present invention.